Disorders of and injuries to the eyes are a significant health concern, particular as the population ages. Major ocular disorders are known to affect the retina, the lens, and/or the cornea of the eyes. Among the most important retinal disorders are macular holes and degeneration, retinal tears, and diabetic retinopathy, to name but a few.
Various ocular disorders are associated with cellular processes such as, but not limited to cellular proliferation, survival, migration, differentiation, and angiogenesis. For example, macular degeneration results from loss of photoreceptors in the portion of the central retina, termed the macula, which is responsible for high-acuity vision. Degeneration of the macula is associated with abnormal deposition of extracellular matrix components in the membrane between the retinal pigment epithelium (RPE) and the vascular choroid. Normal eyes typically have maculas that are free of such deposits, although deposition can be abundant in the retinal periphery. The presence of soft deposits in the macula absent loss of macular vision per se is considered an early stage of age-related macular degeneration (AMD).
AMD is the major cause of severe visual loss in United States citizens over the age of 55. Most AMD patients have a buildup of deposits within and under the RPE in the macular region, which can result in atrophy of the retina and the RPE itself. Normally, retinal pigment cells are long-lived. They serve to scavenge photoreceptor discs from the rods and cones over the course of years, resulting in the accumulation of intracellular wastes. The incompletely digested residues reduce cytoplasmic space in the RPE cells, and can interfere with metabolism. As the cell volume available to the organelles diminishes, the capacity to digest photoreceptors decreases, which might be a factor in the onset and worsening of macular degeneration.
AMD occurs in either an atrophic or an exudative form. In exudative AMD, blood vessels grow from the choriocapillaris through defects in Bruch's membrane and, in some cases, the underlying RPE. Organization of serous or hemorrhagic exudates escaping from these vessels can result in fibrous scarring of the macular region with attendant degeneration of the neuroretina and permanent loss of central vision.
Another important class of ocular condition results from undesirable neovascularization in the eye. Neovascularization is a serious complication of a large variety of ocular disorders affecting the various tissues of the eye because it can lead to blindness. Corneal neovascularization occurs in many conditions and diseases, including trauma, chemical burns, and corneal transplantation.
Corneal transplantation is successful in many patients because of the absence of blood vessels in the corneal tissue. Because there are no blood vessels in the cornea, the circulating components of the immune system are not exposed to the new cornea and there is normally no problem of host-graft rejection. Induction of neovascularization in the cornea would expose the cornea to the immune system and lead to graft rejection. In addition, a subsequent graft is less likely to be successful. Treatments of these various causes of neovascularization can include the administration of immunosuppressives to modulate the inflammatory process, including neovascularization. However, immunosuppressives can inhibit appropriate wound healing in the cornea and can interfere with the ability to fight infections. Delayed wound healing leaves the cornea vulnerable to infections for longer periods. Hence, vision-threatening infections can result from current treatments.
Choroidal neovascularization (CNV) occurs incident to many ocular disorders, and is often associated with the proliferation of choroidal endothelial cells, overproduction of extracellular matrix, and formation of a fibrovascular subretinal membrane. RPE cell proliferation and production of angiogenic factors also appears to affect CNV. Choroidal neovascularization is caused by such retinal disorders as age-related macular degeneration, presumed ocular histoplasmosis syndrome, myopic degeneration, angioid streaks and ocular trauma. Macular degeneration was discussed above. Choroidal neovascularization has proven recalcitrant to treatment in most cases. In only 10% of cases can laser photocoagulation be attempted. There is no other treatment available. Even with successful laser photocoagulation, neovascularization recurs in about 60-70% of eyes.
Neovascularization of the iris, and its attendant scarring can result in glaucoma and blindness. Neovascularization of this portion of the eye can arise as a consequence of diabetic retinopathy, venous occlusion, ocular tumors and retinal detachment. Most commonly, laser treatment to cauterize the blood vessels is tried; however, that has the attendant risk of causing additional scarring.
Retinal and intravitreal neovascularization occurs in a wide range of disorders including diabetic retinopathy, vein occlusions, sickle cell retinopathy, retinopathy of prematurity, retinal detachment, ocular ischemia, and trauma.
Subretinal pigment epithelial and sub-retinal neovascularization are common, yet very severe, disorders of the eye. The growth of new blood vessels interferes with the normal anatomy of the visual and pigmentary cells in the eye, leading to severe visual loss. The new blood vessels leak fluid and blood under the macula causing marked distortion and loss of vision. When these blood vessels develop in the avascular foveal region of the eye, the result is central visual loss and legal blindness.
Absent specific trauma, the specific causes of these types of neovascularization are unknown; however, this disease most often affects patients over the age of 50 years old, who may or may not have a family history of subfoveal neovascularization. The visual loss is usually sufficient to result in legal blindness. There is no proven treatment once the blood vessels invade the foveal region. In fact, there are few warning signs that a patient is developing this disorder and there are no preventative measures. Even under close monitoring by an ophthalmologist, patients with subfoveal neovascularization have a poor prognosis.
Diabetic retinopathy is an ocular disorder that develops secondary to diabetes. It is characterized by thickening of capillary basement membranes and a lack of contact between pericytes and endothelial cells of the capillaries. Loss of pericytes increases leakage of the capillaries, which can lead to a breakdown of the blood-retina barrier.
Proliferative vitreoretinopathy is associated with proliferation of cellular and fibrotic membranes within the vitreous membranes and on the surfaces of the retina. RPE cell proliferation and migration is frequently observed. The membranes associated with proliferative vitreoretinopathy often contain extracellular matrix components such as collagen types I, II, and IV, and fibronectin, and become progressively fibrotic.
Uveitis refers to inflammation of the uveal tract. It includes iritis, cyclitis, and iridocyclitis and choroiditis, and usually occurs with inflammation of additional structures of the eye. This disorder has a variety of causes but is typically treated with systemic steroids, topical steroids, or cyclosporin. The disease frequently presents with a chronic inflammation occurring either in the anterior segment (70%) or in the posterior segment (30%), which can be complicated by episodes of severe exacerbation that frequently is not controllable with conventional medications. Reports in the literature suggest that 30,000 individuals become legally blind each year in the United States from uveitis. In addition, an estimated 20,000 individuals suffer significant loss of visual acuity from this disorder.
Sjogren's syndrome is an immune system disorder which manifests itself in the eyes as conjunctival and corneal dryness (keratoconjunctivitis sicca syndrome), and typically presents as a gritty sensation in the eyes. A lack of tear production resulting from functional destruction of the lacrimal glands by progressive mononuclear cell infiltrate and scarring of the gland. If the cornea is too dry, corneal ulcerations can develop. Current treatments are limited to symptomatic relief of ocular dryness.
The cornea and conjunctiva are also vulnerable to damage from pathogenic agents or direct trauma, drying associated with disorders of tearing, exposure to radiant energy (ultraviolet light, sun and welding guns), allergens such as pollen and mold, and infectious agents. Keratoconjunctivitis can also occur in patients with Stevens-Johnson syndrome, Wegener's granulomatosis, rheumatoid arthritis, atopic dermatitis and cicatricial pemphigoid. Corneal ulcers may occur. Wound healing disorders can also lead to severe ocular tissue damage via activation of inflammatory cells, release of growth factors and cytokines, proliferation and differentiation of ocular cells, increased capillary permeability, alterations in basement membrane matrix composition, increased deposition of extracellular matrix, fibrosis, neovascularization, and tissue remodeling.
For example, after corneal surgery, the cornea must heal. Popular types of corneal surgery include cataract extraction with or without lens replacement; corneal transplants to treat viral infection or penetrating keratoplasty (PKP); glaucoma filtration surgery; and radial keratotomy and other types of surgery to correct refraction. Cataract incisions are typically full thickness wounds in the cornea that can be as large as 8 mm in length with conventional intraocular lenses (IOLs) and as small as 3 mm or less with foldable silicone IOLs. These wounds generally heal without difficulty, although they take several months to stabilize and are associated with warpage of the corneal tissues leading to permanent astigmatism.
Penetrating keratoplasty (PKP) and corneal transplants are also characterized by full-thickness wounds around the entire circumference of the cornea. These wounds tend to remain weak for one or more years. Patients experience drift in visual acuity and increasing risk of wound dehiscence and/or endophthalmitis.
Radial keratotomy (RK) is the most widespread technique for altering the shape of the cornea. A commonly used form of RK places 4-8 surgical incisions in a radial pattern across the cornea. These incisions are typically 70-80% of the depth of the cornea, and are therefore non-penetrating wounds.